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Supported by the International Society for Minimally Invasive Cardiothoracic Surgery (ISMICS), which has received unrestricted educational grants from industries that produce surgical technologies and from the Department of Anesthesia & Perioperative Medicine, Western University, London, ON Canada.

Abstract

Objective: The objectives of this consensus conference were to evaluate the evidence for the efficacy and safety of perioperative drugs, technologies, and techniques in reducing allogeneic blood transfusion for adults undergoing cardiac surgery and to develop evidence-based recommendations for comprehensive perioperative blood management in cardiac surgery, with emphasis on minimally invasive cardiac surgery.

Methods: The consensus panel short-listed the potential topics for review from a comprehensive list of potential drugs, devices, technologies, and techniques. The process of short-listing was based on the need to prioritize and focus on the areas of highest importance to surgeons, anesthesiologists, perfusionists, hematologists, and allied health care involved in the management of patients who undergo cardiac surgery whether through the conventional or minimally invasive approach. MEDLINE, Cochrane Library, and Embase databases were searched from their date of inception to May 2011, and supplemental hand searches were also performed. Detailed methodology and search strategies are outlined in each of the subsequently published systematic reviews. In general, all relevant synonyms for drugs (antifibrinolytic, aprotinin, [Latin Small Letter Open E]-aminocaproic acid, tranexamic acid [TA], desmopressin, anticoagulants, heparin, antiplatelets, anti-Xa agents, adenosine diphosphate inhibitors, acetylsalicylic acid [ASA], factor VIIa [FVIIa]), technologies (cell salvage, miniaturized cardiopulmonary bypass (CPB) circuits, biocompatible circuits, ultrafiltration), and techniques (transfusion thresholds, minimally invasive cardiac or aortic surgery) were searched and combined with terms for blood, red blood cells, fresh-frozen plasma, platelets, transfusion, and allogeneic exposure. The American Heart Association/American College of Cardiology system was used to label the level of evidence and class of each recommendation.

Results and Recommendations: Database search identified more than 6900 articles, with 4423 full-text randomized controlled trials assessed for eligibility, and the final 125 systematic reviews and meta-analyses were used in the consensus conference. The results of the consensus conference, including the evidence-based statements and the recommendations, are outlined in the text, with references given for the relevant evidence that formed the basis for the statements and recommendations.

▪ The lysine analogs [Latin Small Letter Open E]-aminocaproic acid (Amicar) and tranexamic acid (TA) reduce exposure to allogeneic blood in patients undergoing on-pump cardiac surgery. These agents are recommended to be used routinely as part of a blood conservation strategy especially in patients at risk of undergoing on-pump cardiac surgery (Class I, Level A).

▪ It is importarnt not to exceed maximum TA total dosages (50–100 mg/kg) because of potential neurotoxicity in the elderly and open-heart procedures (Class IIb, Level C).

▪ Aprotinin is not recommended in adult cardiac surgery until further studies on its safety profile have been performed (Class III, Level A).

▪ Tranexamic acid dosing in OPCAB surgery needs further study particularly with regard to possible neurotoxicity such as seizures. In addition, the benefit-risk ratio in OPCAB needs further eludication because of the lower inherent risk for bleeding in this group (Class IIb, Level C).

▪ DDAVP can be considered for prophylaxis in coronary artery bypass grafting (CABG) surgery, in particular, for patients on ASA within 7 days or prolonged CPB more than 140 minutes (Class IIa, Level A).

▪ Caution should be used with the DDAVP infusion rate to avoid significant systemic hypotension (Class I, Level A).

▪ The routine use of topical antifibrinolytics in cardiac surgery is not recommended (Class IIa, Level A).

▪ Topical fibrin sealants may be considered in clinical situations where conventional approaches of surgical and medical improvement of hemostasis are not effective, that is, with bleeding problems more local than generalized, bearing in mind the black box warning of bovine thrombin by the US Food and Drug Administration (Class IIb, Level C).

▪ Prophylactic use of FVIIa cannot be recommended because of a significant increase in the risk of thromboembolic events and stroke (Class IIa, Level A).

▪ Factor VIIa may be considered in clinical situations where conventional approaches of surgical and pharmacologic hemostasis have failed and uncontrollable hemorrhage poses a high risk of severe and life-threatening outcomes (Class IIb, Level B).

Recommendations for Erythropoietin Plus Iron:

▪ It is reasonable to administer erythropoietin preoperatively to increase red blood cell mass in patients who are anemic or refuse blood products (such as for Jehovah’s Witness faith) or who are likely to have postoperative anemia (Class IIa, Level A).

▪ Routine use of cell salvage is recommended in operations where an increased blood loss is expected (Class 1, Level A).

▪ Cell salvage should be used throughout the entire operation and not merely as a replacement for CPB cardiotomy suction (Class IIa, Level A).

Recommendations: Biocompatible CPB Circuits:

▪ The routine use of biocompatible coated CPB circuitry may be considered as part of a multimodal blood conservation program. However, the heterogeneity of surface-modified products, anticoagulation management, and CPB technique does not significantly impact surgical blood loss and transfusion needs (Class IIb, Level A).

▪ Although these minimally invasive procedures are not primarily selected for the purpose of blood management, the reduced allogeneic blood exposure should be considered in the balance of benefits and risks when selecting the appropriate surgery for patients.

RATIONALE

Blood loss during and after cardiac surgery is one of the most common causes of allogeneic blood product use.1–3 Blood transfusions are administered during cardiac surgery to manage or prevent hemodynamic instability and ischemia-related injury to the heart, kidneys, brain, and other vital organs. Administration of red blood cells (RBCs) may improve oxygen delivery when the existing RBC mass has been depleted. Other blood product fractions including plasma, cryoprecipitate, and platelets may reduce coagulopathies.4–7 However, oxygen delivery and coagulopathies are not hard outcomes per se, and it is the prevention of clinically relevant adverse outcomes such as death, stroke, myocardial infarction, renal failure, infection, and blood loss requiring intervention that would be of greater clinical relevance. Whether transfusions adequately prevent these clinically relevant outcomes to a degree that matter, and with sufficient magnitude that the benefits outweigh the inherent risks that accompany blood product transfusion, remains a relevant and timely question.7,8

A myriad of studies (observational studies and randomized trials) have demonstrated an adverse and dose-related association between blood product transfusion and serious morbidity and mortality in surgical and critical care patients.7,9–11 As a result, uncertainty remains regarding the rightful place for blood product transfusions (in whom, at what threshold, and after failing which alternatives?).12–14 Clearly, the risks of blood product administration, considered together with the uncertain benefits, significant costs, and limited supply of blood products, suggest that blood administration should not be considered lightly and conservation practices need to be ascertained and agreed on.

Whereas the clinically appropriate place of blood product transfusion has been uncertain in the world of conventional cardiac surgery, it remains even less certain within the world of minimally invasive cardiac surgery where the risk for blood loss and hemodilution is likely to be inherently less than in conventional surgery. The International Society of Minimally Invasive Cardiothoracic Surgery (ISMICS) sponsored this consensus conference to specifically address the evidence for blood conservation in cardiac surgery, with special emphasis on minimally invasive cardiac surgery. This consensus statement was convened to add to existing guidelines on cardiac surgical blood management strategies7,15–20 because previous guidelines have not specifically addressed blood management for minimally invasive cardiac surgery.

The methodology used to support the evidence identification, retrieval, synthesis, and interpretation for this consensus panel was similar to previous published ISMICS consensus conferences.21–29 This represents the eighth consensus conference supported by ISMICS. Previous consensus statements are freely available at www.ismics.org.

SEARCH STRATEGY AND EVIDENCE RETRIEVAL

For each aspect of perioperative blood management to be addressed during the consensus conference, we searched for existing high-quality systematic reviews of the literature to objectively inform the consensus panel. If high-quality published systematic reviews were not found or if they did not include the most recent studies, de novo systematic reviews were performed by members of the group for publication in the peer-reviewed literature. The de novo systematic reviews were performed in accordance with recent guidelines for evidence synthesis.30 MEDLINE, Cochrane Library, and Embase databases were searched from their date of inception to May 2011, and supplemental hand searches were also performed. Detailed methodology and search strategies are outlined in each of the subsequently published systematic reviews. In general, all relevant synonyms for drugs (antifibrinolytic, aprotinin [AP], [Latin Small Letter Open E]-aminocaproic acid [EACA], tranexamic acid [TA], desmopressin, anticoagulants, heparin, antiplatelets, anti-Xa agents, adenosine diphosphate inhibitors, acetylsalicylic acid [ASA, aspirin], factor VIIa [FVIIa]), technologies (cell salvage [CS], miniaturized cardiopulmonary bypass [CPB] circuits, biocompatible circuits, ultrafiltration), and techniques (transfusion thresholds, minimally invasive cardiac or aortic surgery) were searched and were combined with terms for blood, RBCs, fresh-frozen plasma (FFP), platelets, transfusion, and allogeneic exposure.

Identification, selection, and quality assessment of relevant studies (meta-analyses, systematic reviews, randomized trials, and if needed, based on lack of higher levels of evidence, observational studies) was performed by at least two reviewers based on predefined inclusion criteria (published in any language, with relevant patient population, intervention, comparator, and outcomes for the prespecified clinical questions). Noncomparative studies were not considered. Data were extracted and double checked by a team of systematic reviewers. Meta-analysis was performed using the random effects model when heterogeneity across studies was expected to be significant or using the fixed effect model when heterogeneity was not statistically significant. Using Review Manager 5, Stata, or Comprehensive Meta-Analysis v2.0, the weighted mean differences (WMDs) and 95% confidence intervals (95% CIs) for continuous data and the rate ratio (95% CI) for dichotomous data were calculated. Meta-regressions were performed when dose-response relationships were in question or when time-dependent outcomes were in question. Heterogeneity across studies was estimated using the I2 statistic, whereby an I2 exceeding 50% was considered moderately heterogeneous and I2 exceeding 75% was considered highly heterogeneous.

LEVELS OF EVIDENCE AND GRADES OF RECOMMENDATIONS

As described in previous ISMICS consensus statements,21–29 the evidence used in consideration for each respective clinical question and any related subquestions was classified according to the American Heart Association (AHA)/American College of Cardiology (ACC) levels of evidence and grades of recommendation (Tables 1 and 2). The AHA/ACC classification categorizes evidence levels primarily based on considerations of study design where the highest level of evidence (Level A) consists of two or more randomized controlled trials. We also include meta-analyses of randomized trials as Level A evidence. The higher the level of evidence has presumably, the lesser the likelihood for bias caused by trial design limitations.31,32 However, it is also important to consider that there are additional forms of bias beyond the study design alone, which should be considered when applying evidence to make recommendations.32

While other systems of grading evidence exist, the AHA/ACC system was used to maintain consistency with previous consensus statements21–29 and to allow comparability with other AHA/ACC statements in the field of cardiology and cardiac surgery. Labeling the level of evidence for each statement and classifying the recommendations derived from the evidence statements were performed collaboratively with the consensus panel using a democratic process after full discussion of the strengths and limitations of the evidence. The highest existing level of evidence was considered when making recommendations to inform the clinical questions, whereby systematic reviews and meta-analyses of randomized trials (Level A) were considered preferentially over singular randomized trials or observational studies (Level B). When no relevant clinical trials could be found after systematically reviewing the literature, expert opinion from the consensus panel was considered but was labeled explicitly as such so the reader will interpret it flexibly in full light of the lack of evidence and reliance on opinion (Level C evidence). Recommendations with highest levels of evidence should be interpreted with more confidence than recommendations based on lower levels of evidence. The former recommendations may represent a list of priorities for implementation into practice after consideration of local contextual factors, whereas the latter (Level B and Level C) should be considered to be important priorities for future research programs to clarify the existing gaps in the evidence to move beyond reliance on opinion.

SELECTION OF TOPICS FOR REVIEW

The consensus panel short-listed the topics for review from a comprehensive list of potential drugs, devices, technologies, and techniques. The process of short-listing was based on the practical need to prioritize and focus on the areas of highest importance to cardiac surgeons, anesthesiologists, perfusionists, hematologists, and allied health care involved in the management of patients who undergo cardiac surgery whether through the conventional or the minimally invasive approach. The purpose of this consensus conference was to give an overview of the role of drugs, technologies, and techniques for blood management in the setting of minimally invasive and conventional cardiac surgery.

RESULTS

Database search identified more than 6900 articles, with 4423 full-text randomized controlled trials (RCTs) assessed for eligibility, and the final 125 systematic reviews and meta-analyses were used in the consensus conference. The results of the consensus conference, including the evidence-based statements and the recommendations, are outlined below, with references given for the relevant evidence that formed the basis for the statements and recommendations. Readers are encouraged to consult the original publications for the systematic reviews and meta-analyses for the detailed discussion of outcomes and implications for each of the drugs, technologies, and techniques discussed below.

6. Preliminary evidence from case series has raised considerations about potential neurotoxicity with TA (seizures, particularly exceeding the higher doses); further research about safe dosing levels remains to be addressed in valid studies (Level C).

Recommendations for TA in OPCAB

▪ Tranexamic acid may be recommended as part of a blood conservation strategy in high-risk patients undergoing OPCAB surgery (Class I, Level A).

▪ Tranexamic acid dosing in OPCAB surgery needs further study particularly with regard to possible neurotoxicity such as seizures. In addition, the benefit-risk ratio in OPCAB needs further eludication because of the lower inherent risk for bleeding in this group (Class IIb, Level C).

Relevant Evidence

Statements for DDAVP

1. DDAVP prophylaxis has been shown to reduce blood loss; however, its effect on need for blood transfusion does not reach conventional significance and the effect is heterogeneous across trials (Level A).

Recommendations for Topical Hemostatics

▪ Routine use of topical antifibrinolytics in cardiac surgery is not recommended (Class IIa, Level A).

▪ Topical fibrin sealants may be considered in clinical situations where conventional approaches of surgical and medical improvement of hemostasis are not effective, that is, with bleeding problems more local than generalized, bearing in mind the black box warning of bovine thrombin by the US Food and Drug Administration (Class IIb, Level C)

Recommendations for FVIIa

▪ Prophylactic use of FVIIa cannot be recommended because of a significant increase in the risk of thromboembolic events and stroke (Class IIa, Level A).

▪ Factor VIIa may be considered in clinical situations where conventional approaches of surgical and pharmacologic hemostasis have failed and uncontrollable hemorrhage poses a high risk of severe and life-threatening outcomes (Class IIb, Level B).

Statements for Erythropoietin Plus Iron

1. Erythropoietin (EPO) reduces the risk of allogeneic RBC exposure (OR, 0.26; 95% CI, 0.15–0.44; number needed to treat, 4) in cardiac surgery undergoing PAD and in patients not undergoing PAD for cardiac surgery (Level A); however, its impact on AMI, RF, cerebrovascular accident (CVA), and death is unknown.

2. Although the impact may be greater when EPO is initiated 2 to 4 weeks before surgery, emerging evidence suggests that EPO initiated on the day of surgery may also reduce the need for transfusion (Level A).

3. In OPCAB, EPO (high-dose, short-term) reduced the risk of RBC transfusion (Level B); however, its impact on AMI, RF, CVA, and death is unknown.

4. Reports of improvement in neurologic outcomes and reduced acute kidney injury (Level B) are encouraging, but more study is needed.

Recommendations for EPO Plus Iron

▪ It is reasonable to administer EPO preoperatively to increase red blood cell mass in patients who are anemic or refuse blood products (such as for Jehovah’s Witness faith) or who are likely to have postoperative anemia (Class IIa, Level A).

Nijjer S. Safety of clopidogrel being continued until the time of coronary artery bypass grafting in patients with acute coronary syndrome: a meta-analysis of 34 studies. Euro Heart J. 2011 (Epub ahead of print).

Statements for Antiplatelets After Cardiac Surgery

1. Post-CABG use of clopidogrel with ASA is associated with increased trend for major and minor bleeding but no clear benefits on clinical outcomes (MI, stroke, death) after CABG surgery in on-pump and OPCAB patients (Level B).

Recommendations: Biocompatible Coated CPB Circuits

▪ The routine use of biocompatible coated CPB circuitry may be considered as part of a multimodal blood conservation program. However, the heterogeneity of surface-modified products, anticoagulation management, and CPB technique does not significantly impact surgical blood loss and transfusion needs (Class IIb, Level A).

○ A number of existing studies did not clearly define membrane “biocompatibility,” and existing trials have tested heterogeneous biocompatible membranes. Studies need to clarify the membrane and the concomitant therapies (ie, coated oxygenator only or whole circuit? which biocoat? open vs closed reservoir? differences in heparinization?) and will need to adequately evaluate which characteristics provide best outcomes.

MECC Versus OPCAB

1. Miniaturized extracorporeal cardiopulmonary circuit and OPCAB provide similar risks of blood loss and allogeneic transfusion. Clinical outcomes have not been shown to differ between MECC and OPCAB (Level A [two small RCTs; four observational studies]).

▪ Miniaturized extracorporeal cardiopulmonary circuit can be considered as a blood conservation technique to reduce allogeneic blood exposure (Class IIa, Level A); however, issues related to heparinization management and biocoat remain to be clarified.

Statements: POC Monitoring

1. Despite benefits shown for thromboelastography/thromboelastometry for reduced blood subcomponent transfusion, the results are heterogeneous and no benefit has been shown for clinically relevant outcomes (Level A).

2. The technologies for POC are still evolving, and adequate experience and evidence from clinical trials are required. In addition, the initial evidence that platelet testing impacts on decision making also requires confirmation of positive clinical impact (Level C).

Recommendations for POC Monitoring

Recommendations for Future Research Related to POC Monitoring

○ Randomized controlled trials that are adequately powered to measure clinically relevant outcomes such as death, stroke, MI, interventions for bleeding, and cost-effectiveness are required.

○ Further studies should aim for consistency in which monitor is used and how they are used to direct decision making (ie, when and how frequently to measure platelet function perioperatively? When do the results add to standard anticoagulant monitoring? What actions should be taken based on the results of the POC monitoring?

○ Is one monitoring system superior to another? How do the newer anticoagulants and antiplatelet agents impact the monitoring protocols?

Statements for TAVI

2. However, the balance of benefits and risks with respect to other clinically relevant outcomes is of key interest. There was similar 30-day and 1-year mortality but increased risk of stroke at 30 days (5.5% vs 2.4%) and 1 year (8.3% vs 4.3%) (Level B, one RCT).

Recommendations for Surgical Techniques for OPCAB, Mini-AVR, Mini-MVR, and TAVI

▪ Whereas these minimally invasive procedures are not primarily selected for the purpose of blood management, the reduced allogeneic blood exposure should be considered in the balance of benefits and risks when selecting the appropriate surgery for patients.

DISCUSSION

A number of drugs, technologies, and techniques have been shown to reduce the need for allogeneic blood transfusion and should be routinely considered as part of a program to reduce exposure to allogeneic blood, including lysine analogs, discontinuing antiplatelets in non-ACS patients and in patients without recent DESs, RAP, and use of CS throughout surgery (see summary in Table 3). The benefits of other strategies remain less clear, and definitive recommendations for routine use would be premature (ie, topical hemostatics, DDAVP, FVIIa in refractory bleeding, EPO, ANH, biocom patible CPB circuits, MECC, ultrafiltration, platelet plasmapheresis, POC platelet function testing). Furthermore, the role of the minimally invasive approach to surgery may be part of a program to reduce blood loss; however, there are more important considerations for choosing between minimally invasive and conventional approaches to cardiac surgery.

It is notable that none of these approaches to blood conservation has been proven in RCTs to significantly improve clinically important outcomes such as death, stroke, or organ failure in randomized trials. Furthermore, few of these approaches to blood conservation have been adequately addressed to determine their impact when applied singularly versus in combination as a multimodal approach to conservation. If the primary purpose of blood conservation strategies is to reduce the risk of clinically meaningful adverse events caused by blood exposure (presumably, increased risk of death, morbidities, immunologic reactions, and infections) while balancing the risk of anemia (death, stroke, MI, organ failure), then it is surprising that so few randomized trials have addressed these outcomes. Most RCTs have measured exposure to allogeneic blood, or volume of blood transfused, rather than measuring the ultimate outcomes that matter most to patients. While conserving blood because of limitations in supply is important, it is not the ultimate outcome per se, and future research is imperative to address whether strategies to reduce blood transfusion result in comparable or improved rates of death, stroke, MI, RF, neurologic function, graft patency, and overall serious adverse events.

If there has been a dearth of evidence for clinically relevant outcomes in conventional cardiac surgery, there has been an even greater lack of evidence addressing these important questions for minimally invasive cardiac surgery. The latter represents an important call to action for surgeons, anesthesiologists, perfusionists, intensivists, and other health care professionals to prioritize research on these most important questions. More than 1 million cardiac surgeries are performed globally every year, and still a paucity of research exists to support evidence-based decision making for patient care in safety and cost-effectiveness in blood management.

Areas Not Addressed

A number of important areas related to blood conservation were not addressed during this consensus conference, recognizing that future consensus processes may address these areas, such as the role of colloids versus crystalloids for fluid management, restrictive versus standard or liberal transfusion thresholds, role of transfusing different blood fractions (FFP, platelets, cryoprecipitate), role of different anticoagulation strategies (different doses of heparin, different ACT targets, protamine reversal strategies, and different classes of anticoagulants such as bivalirudin for anticoagulation during cardiac surgery, whether for on-pump or off-pump surgery). In addition, the role of formal blood management programs at the institutional and regional level was not specifically addressed during this consensus conference.33–36

Cost-effectiveness, Availability, and Local Contextual Considerations

This consensus panel did not specifically address issues of cost-effectiveness, and this should not be interpreted to suggest that costs and resource considerations are not important. Because cost-effectiveness and resource considerations are context-sensitive, these issues should be considered locally before decisions are made about the relative appropriateness of the different drugs, technologies, and techniques. In addition, local considerations regarding the availability of the drugs and technologies will be an important driver for deciding which is most important. Lastly, local expertise and skill sets should be considered carefully when deciding which type of surgical technique is appropriate, given that the learning curve can be a significant driver of adverse clinical outcomes, including a higher risk for bleeding.

CONCLUSIONS

A number of strategies have been shown to reduce the need for allogeneic blood transfusion in patients undergoing conventional cardiac surgery (antifibrinolytics such as lysine analogs, discontinuation of clopidogrel preoperatively in non-ACS patients without recent DESs, RAP, intraoperative CS), and these should be encouraged for routine blood conservation management. A number of strategies to conserve blood remain nondefinitive because of lack of consistent evidence (topical hemostatics, DDAVP, FVIIa in refractory bleeding, EPO, ANH, biocompatible CPB circuits, MECC, ultrafiltration, platelet plasmapheresis, POC platelet function testing). A number of strategies not addressed in this review should be the focus of future consensus, including anticoagulation strategies, colloids versus crystalloids, restrictive transfusion thresholds, transfusion protocols, and effective implementation of multifaceted blood conservation programs. Few blood management strategies have been specifically tested in minimally invasive cardiac surgery. The lack of high-level evidence to address the impact on clinical outcomes such as infection, incompatibility immunologic reactions, kidney failure, MI, stroke, and death remains a significant barrier to determining which drugs, technologies, and techniques provide worthy improvements in clinically important outcomes for patients undergoing cardiac surgery whether conventional or minimally invasive. Given the volume of cardiac surgery that is performed around the world and the significant consumption of blood that occurs during cardiac surgery, future large-scale research should be conducted to address these questions.

ACKNOWLEDGMENTS

The authors acknowledge the support for extensive literature searches and article retrievals from Brieanne McConnell, MLIS. In addition, Avtar Lal, MD, PhD, and Junseok Jeon, MD, PhD, provided data analysis for a number of systematic review updates from the Western University. The authors also acknowledge the organizational support of Aurelie Alger and Elizabeth Chouinard from ISMICS to facilitate distribution of the collected literature and the face-to-face meeting for the consensus panel. This consensus conference was cochaired by Dr Alan H. Menkis and Dr Niv Ad.

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